Role of nucleus accumbens microRNA-181a and MeCP2 in incubation of heroin craving in male rats.

RATIONALE: Epigenetic regulation has been implicated in the incubation of drug craving (the time-dependent increase in drug seeking after prolonged withdrawal from drug self-administration). There is little information available on the role of microRNAs in incubation of heroin craving.

OBJECTIVE

This study aimed to investigate the roles and mechanisms of miR-181a and methyl CpG binding protein 2 (MeCP2) in the nucleus accumbens (NAc) in incubation of heroin seeking.

METHODS

MiRNA sequencing was used to predict potential miRNAs, and miRNA profiles were performed in the NAc after 1 day or 14 days after withdrawal from heroin self-administration. Following 14 days of heroin self-administration, rats were injected of lentiviral vectors into the NAc and evaluated for the effects of overexpression of miR-181a or knockdown of MeCP2 on non-reinforced heroin seeking after 14 withdrawal days.

RESULTS

Lever presses during the heroin-seeking tests were higher after 14 withdrawal days than after 1 day (incubation of heroin craving). miR-181a expression in NAc was lower after 14 withdrawal days than after 1 day, and meCP2 expression in NAc was higher after 14 days than after 1 day. Luciferase activity assay showed that the 3'UTR of MeCP2 is directly regulated by miR-181a. Overexpression of miR-181a in NAc decreased heroin seeking after 14 withdrawal days and decreased MeCP2 mRNA and protein expression. Knockdown of MeCP2 expression in NAc by LV-siRNA-MeCP2 also decreased heroin seeking after 14 withdrawal days.

CONCLUSIONS

Results indicate that incubation of heroin craving is mediated in part by time-dependent decreases in NAc miR181a expression that leads to time-dependent increases in MeCP2 expression. Our data suggest that NAc miR-181a and MeCP2 contribute to incubation of heroin craving.